Читать книгу Medical Pharmacology at a Glance - Michael J. Neal - Страница 13
Оглавление2 Drug–receptor interactions
The tissues in the body have only a few basic responses when exposed to agonists (e.g. muscle contraction, glandular secretion), and the quantitative relationship between these physiological responses and the concentration of the agonist can be measured by using bioassays. The first part of the drug–receptor interaction, i.e. the binding of drug to receptor, can be studied in isolation using binding assays.
It has been found by experiment that, for many tissues and agonists, when the response is plotted against the concentration of the drug, a curve is produced that is often hyperbolic (concentration–response curve, top left). In practice, it is often more convenient to plot the response against the logarithm of the agonist concentration (log concentration–response curve, middle top). Assuming that the interaction between the drug (A) and the receptor (R) (lower figure) obeys the law of mass action, then the concentration of the drug–receptor complex (AR) is given by:
where RO = total concentration of receptors, A = agonist concentration, KD = dissociation constant and AR = concentration of occupied receptors.
As this is the equation for a hyperbola, the shape of the dose–response curve is explained if the response is directly proportional to [AR]. Unfortunately, this simple theory does not explain another experimental finding – some agonists, called partial agonists, cannot elicit the same maximum response as full agonists even if they have the same affinity for the receptor (top left and middle, ). Thus, in addition to having affinity for the receptor, an agonist has another chemical property, called intrinsic efficacy, which is its ability to elicit a response when it binds to a receptor (lower figure).
A competitive antagonist has no intrinsic efficacy and, by occupying a proportion of the receptors, effectively dilutes the receptor concentration. This causes a parallel shift of the log concentration–response curve to the right (top right, ), but the maximum response is not depressed. In contrast, irreversible antagonists depress the maximum response (top right, ). However, at low concentrations, a parallel shift of the log concentration–response curve may occur without a reduction in the maximum response (top right, ). Because an irreversible antagonist in effect removes receptors from the system, it is clear that not all of the receptors need to be occupied to elicit the maximum response (i.e. there is a receptor reserve).
Binding of drugs to receptors
Intermolecular forces
Drug molecules in the environment of receptors are attracted initially by relatively long‐range electrostatic forces. Then, if the molecule is suitably shaped to fit closely to the binding site of the receptor, hydrogen bonds and van der Waals forces briefly bind the drug to the receptor. Irreversible antagonists bind to receptors with strong covalent bonds.
Affinity
This is a measure of how avidly a drug binds to its receptor. It is characterized by the equilibrium dissociation constant (KD), which is the ratio of rate constants for the reverse (k−1) and forward (k+1) reactions between the drug and the receptor. The reciprocal of KD is called the affinity constant (KA), and (in the absence of receptor reserve, see below) is the concentration of drug that produces 50% of the maximum response.
Antagonists
Most antagonists are drugs that bind to receptors but do not activate them. They may be competitive or irreversible. Other types of antagonists are less common.
Competitive antagonists bind reversibly with receptors, and the tissue response can be returned to normal by increasing the dose of agonist, because this increases the probability of agonist–receptor collisions at the expense of antagonist–receptor collisions. The ability of higher doses of agonist to overcome the effects of the antagonist results in a parallel shift of the dose–response curve to the right and is the hallmark of competitive antagonism.
Irreversible antagonists have an effect that cannot be reversed by increasing the concentration of agonist. The only important example is phenoxybenzamine, which binds covalently with α‐adrenoceptors. The resulting insurmountable block is valuable in the management of phaeochromocytoma, a tumour that releases large amounts of epinephrine (adrenaline).
Other types of antagonism
Non‐competitive antagonists do not bind to the receptor site but act downstream to prevent the response to an agonist, e.g. calcium‐channel blockers (Chapter 15).
Chemical antagonists simply bind to the active drug and inactivate it, e.g. protamine abolishes the anticoagulant effect of heparin (Chapter 19).
Physiological antagonists are two agents with opposite effects that tend to cancel one another out, e.g. prostacyclin and thromboxane A2 on platelet aggregation (Chapter 19).
Receptor reserve
In some tissues (e.g. smooth muscle), irreversible antagonists initially shift the log dose–response curve to the right without reducing the maximum response, indicating that the maximum response can be obtained without the agonist occupying all the receptors. The excess receptors are sometimes called ‘spare’ receptors, but this is a misleading term because they are of functional significance. They increase both the sensitivity and speed of a system because the concentration of drug–receptor complex (and hence the response) depends on the product of the agonist concentration and the total receptor concentration.
Partial agonists
These are agonists that cannot elicit the same maximum response as a ‘full’ agonist. The reasons for this are unknown. One suggestion is that agonism depends on the affinity of the drug–receptor complex for a transducer molecule (lower figure). Thus, a full agonist produces a complex with high affinity for the transducer (e.g. the coupling G‐proteins, Chapter 1), whereas a partial agonist–receptor complex has a lower affinity for the transducer and so cannot elicit the full response.
When acting alone at receptors, partial agonists stimulate a physiological response, but they can antagonize the effects of a full agonist. This is because some of the receptors previously occupied by the full agonist become occupied by the partial agonist, which has a smaller effect (e.g. some β‐adrenoceptor antagonists, Chapters 15 and 16).
Intrinsic efficacy
This is the ability of an agonist to alter the conformation of a receptor in such a way that it elicits a response in the system. It is defined as the affinity of the agonist–receptor complex for a transducer.
Partial agonists and receptor reserve. A drug that is a partial agonist in a tissue with no receptor reserve may be a full agonist in a tissue possessing many ‘spare’ receptors, because its poor efficacy can be offset by activating a larger number of receptors than that required by a full agonist.
Bioassay
Bioassays involve the use of a biological tissue to relate drug concentration to a physiological response. Usually isolated tissues are used because it is then easier to control the drug concentration around the tissue and reflex responses are abolished. However, bioassays sometimes involve whole animals, and the same principles are used in clinical trials.
Bioassays can be used to estimate:
the concentration of a drug (largely superseded by chemical methods);
its binding constants; or
its potency relative to another drug.
Measurement of the relative potencies of a series of agonists on different tissues has been one of the main ways used to classify receptors, e.g. adrenoceptors (Chapter 7).
Binding assays
Binding assays are simple and very adaptable. Membrane fragments from homogenized tissues are incubated with radiolabelled drug (usually 3H) and then recovered by filtration. After correction for non‐specific binding, the [3H]drug bound to the receptors can be determined and estimations made of KA and Bmax (number of binding sites). Binding assays are widely used to study drug receptors, but have the disadvantage that no functional response is measured, and often the radiolabelled drug does not bind to a single class of receptor.
Localization of receptors
The distribution of receptors, e.g. in sections of the brain, can be studied using autoradiography. In humans, positron‐emitting drugs can sometimes be used to obtain images (positron emission tomography [PET] scanning) showing the location and density of receptors, e.g. dopamine receptors in the brain (Chapter 27).
Tachyphylaxis, desensitization, tolerance and drug resistance
When a drug is given repeatedly, its effects often decrease with time. If the decrease in effect occurs quickly (minutes), it is called tachyphylaxis or desensitization. Tolerance refers to a slower decrease in response (days or weeks). Drug resistance is a term reserved for the loss of effect of chemotherapeutic agents, e.g. antimalarials (Chapter 43). Tolerance may involve increased metabolism of a drug, e.g. ethanol, barbiturates (Chapter 3), or homeostatic mechanisms (usually not understood) that gradually reduce the effect of a drug, e.g. morphine (Chapter 29). Changes in receptors may cause desensitization, e.g. suxamethonium (Chapter 6). A decrease in receptor number (downregulation) can lead to tolerance, e.g. insulin (Chapter 36).
